The emergence of multiply antibiotic resistant bacteria threatens the efficacy of antibiotics in combating infectious diseases. Among diverse microbial antibiotic resistance mechanisms, the mar regulon of Escherichia coli is unique in that it is inducible by agents used in clinical situations; the antibiotics chloramphenicol and tetracycline and aromatic week acids such as salicylate and acetylsalicylate. These agents counter the marR-encoded repression of the marRAB operon; the induced MarA product then activates transcription of a dozen diverse genes (the mar regulon) leading to multiple antibiotic and superoxide resistances. We have now provided a mechanistic basis for these actions by purifying MarR and MarA proteins and studying their interaction with DNA in vitro. MarR was found to bind the mar promoter at 2 sets of sequences, 1 of which is likely to prevent mar transcription. Salicylate bound to MarR and decreased its affinity for the mar promoter DNA. MarA enhanced the transcription of various mar regulon promoters in a purified in vitro transcription system. MarA also bound specifically to a "marbox" sequence in the mar promoter region. Deletions of this and adjacent sequences affected mar promoter activity in vitro and in vivo. Thus, MarR and MarA regulate the operon both negatively and positively, perhaps to enable rapid shut-down and start-up of the system. B. We previously described the susceptibility of peroxidase mutants of E. coli and Salmonella typhimurium to isoniazid (INH), a clinically important antituberculosis drug. We now find that INH induces athe SOS response: induction of lambda prophage, cellular filamentation, sulA expression, and mutation in the Ames Test. Since SOS is induced by agents that make single-stranded breaks in DNA, this implies that INH can damage DNA. It remains to be seen whether INH is mutagenic for Mycobacterium tuberculosis and whether it enhances the emergence of antibiotic resistant mutants.